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Ciliopathies

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https://www.readbyqxmd.com/read/29771326/basal-exon-skipping-and-nonsense-associated-altered-splicing-allows-bypassing-complete-cep290-loss-of-function-in-individuals-with-unusually-mild-retinal-disease
#1
Iris Barny, Isabelle Perrault, Christel Michel, Mickael Soussan, Nicolas Goudin, Marlène Rio, Sophie Thomas, Tania Attié-Bitach, Christian Hamel, Hélène Dollfus, Josseline Kaplan, Jean-Michel Rozet, Xavier Gerard
CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base-pair deletion in exon 17, introducing a premature termination codon (PTC) in exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls...
May 16, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29771182/ciliogenesis-is-reciprocally-regulated-by-ppara-and-nr1h4-fxr-through-controlling-autophagy-in-vitro-and-in-vivo
#2
Zhi-Qiang Liu, Joon No Lee, Myeongjoo Son, Jae-Young Lim, Raghbendra Kumar Dutta, Yunash Maharjan, SeongAe Kwak, Goo Taeg Oh, Kyunghee Byun, Seong-Kyu Choe, Raekil Park
The primary cilia are evolutionarily conserved microtubule-based cellular organelles that perceive metabolic status and thus link the sensory system to cellular signaling pathways. Therefore, ciliogenesis is thought to be tightly linked to autophagy, which is also regulated by nutrient-sensing transcription factors, such as PPARA (peroxisome proliferator activated receptor alpha) and NR1H4/FXR (nuclear receptor subfamily 1, group H, member 4). However, the relationship between these factors and ciliogenesis has not been clearly demonstrated...
May 17, 2018: Autophagy
https://www.readbyqxmd.com/read/29754569/toward-personalized-medicine-in-bardet-biedl-syndrome
#3
Joanna Kenny, Elizabeth Forsythe, Philip Beales, Chiara Bacchelli
Personalized medicine is becoming routine in the treatment of common diseases such as cancer, but has lagged behind in the field of rare diseases. It is currently in the early stages for the treatment of Bardet-Biedl syndrome. Advances in the understanding of ciliary biology and diagnostic techniques have opened up the prospect of treating BBS in a patient-specific manner. Owing to their structure and function, cilia provide an attractive therapeutic target and genetic therapies are being explored in ciliopathy treatment...
September 2017: Personalized Medicine
https://www.readbyqxmd.com/read/29742051/interaction-of-wdr60-intermediate-chain-with-tctex1d2-light-chain-of-the-dynein-2-complex-is-crucial-for-ciliary-protein-trafficking
#4
Yuki Hamada, Yuta Tsurumi, Shohei Nozaki, Yohei Katoh, Kazuhisa Nakayama
The dynein-2 complex mediates trafficking of ciliary proteins by powering the intraflagellar transport (IFT) machinery containing IFT-A and IFT-B complexes. Although 11 subunits are known to constitute the dynein-2 complex, with several light chain subunits shared by the dynein-1 complex, the overall architecture of the dynein-2 complex has not been fully clarified. Utilizing the visible immunoprecipitation assay, we demonstrated the interaction modes among the dynein-2 subunits, including previously undefined interactions, such as that between WDR60 and the TCTEX1D2-DYNLT1/DYNLT3 dimer...
May 9, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29742019/the-e3-ubiquitin-ligase-ubr5-regulates-centriolar-satellite-stability-and-primary-cilia
#5
Robert F Shearer, Kari-Anne Myrum Frikstad, Jessie McKenna, Rachael A McCloy, Niantao Deng, Andrew Burgess, Trond Stokke, Sebastian Patzke, Darren N Saunders
Primary cilia are crucial for signal transduction in a variety of pathways, including Hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The Ubiquitin-Proteasome System (UPS) component UBR5 was previously identified as a putative positive regulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 Ubiquitin ligase that is frequently deregulated in tumours, but its biological role in cancer is largely uncharacterised, partly due to a lack of understanding of interacting proteins and pathways...
May 9, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29741480/a-novel-cep120-dependent-mechanism-inhibits-centriole-maturation-in-quiescent-cells
#6
Ewelina Betleja, Rashmi Nanjundappa, Tao Cheng, Moe R Mahjoub
The two centrioles of the centrosome in quiescent cells are inherently asymmetric structures that differ in age, morphology and function. How these asymmetric properties are established and maintained during quiescence remains unknown. Here we show that a daughter centriole-associated ciliopathy protein, Cep120, plays a critical inhibitory role at daughter centrioles. Depletion of Cep120 in quiescent mouse and human cells causes accumulation of pericentriolar material (PCM) components including Pericentrin, Cdk5Rap2, Ninein and Cep170...
May 9, 2018: ELife
https://www.readbyqxmd.com/read/29734148/new-insights-into-cystic-kidney-diseases
#7
Toshio Mochizuki, Shiho Makabe, Yumi Aoyama, Hiroshi Kataoka, Kosaku Nitta
Hereditary cystic kidney diseases are considered as "ciliopathies" caused by abnormalities of the "primary cilia" situated on the tubules. As a result of dysplasia and dysfunction of cilia, formation of cysts occurs at various stages of life. Although occurring at a low incidence, hereditary cystic kidney diseases that develop from the fetal stage to childhood are diverse and are often associated with systemic disorders. The incidence of autosomal dominant polycystic kidney disease, which is the only adult-onset hereditary cystic kidney disease, is the highest among hereditary renal disorders...
2018: Contributions to Nephrology
https://www.readbyqxmd.com/read/29727300/rab23-and-developmental-disorders
#8
Catherine H H Hor, Bor Luen Tang, Eyleen L K Goh
Rab23 is a conserved member of the Rab family of small GTPases that regulates membrane trafficking in eukaryotes. It is unique amongst the Rabs in terms of its implicated role in mammalian development, as originally illustrated by the embryonic lethality and open neural tube phenotype of a spontaneous mouse mutant that carries homozygous mutation of open brain, a gene encoding Rab23. Rab23 was initially identified to act as an antagonist of Sonic hedgehog (Shh) signaling, and has since been implicated in a number of physiological and pathological roles, including oncogenesis...
May 4, 2018: Reviews in the Neurosciences
https://www.readbyqxmd.com/read/29725084/loss-of-tctn3-causes-neuronal-apoptosis-and-neural-tube-defects-in-mice
#9
Bin Wang, Yingying Zhang, Hongli Dong, Siyi Gong, Bin Wei, Man Luo, Hongyan Wang, Xiaohui Wu, Wei Liu, Xingshun Xu, Yufang Zheng, Miao Sun
Tctn3 belongs to the Tectonic (Tctn) family and is a single-pass membrane protein localized at the transition zone of primary cilia as an important component of ciliopathy-related protein complexes. Previous studies showed that mutations in Tctn1 and Tctn2, two members of the tectonic family, have been reported to disrupt neural tube development in humans and mice, but the functions of Tctn3 in brain development remain elusive. In this study, Tctn3 knockout (KO) mice were generated by utilizing the piggyBac (PB) transposon system...
May 3, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29721959/binary-function-of-arl3-gtp-revealed-by-gene-knockouts
#10
Christin Hanke-Gogokhia, Jeanne M Frederick, Houbin Zhang, Wolfgang Baehr
UNC119 and PDEδ are lipid-binding proteins and are thought to form diffusible complexes with transducin-α and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29720996/rare-compound-heterozygous-frameshift-mutations-in-alms1-gene-identified-through-exome-sequencing-in-a-taiwanese-patient-with-alstr%C3%A3-m-syndrome
#11
Meng-Che Tsai, Hui-Wen Yu, Tsunglin Liu, Yen-Yin Chou, Yuan-Yow Chiou, Peng-Chieh Chen
Alström syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29717526/nephronophthisis-a-review-of-genotype-phenotype-correlation
#12
REVIEW
Fenglan Luo, Yuhong Tao
Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed...
May 1, 2018: Nephrology
https://www.readbyqxmd.com/read/29706353/patient-ipsc-derived-kidney-organoids-show-functional-validation-of-a-ciliopathic-renal-phenotype-and-reveal-underlying-pathogenetic-mechanisms
#13
Thomas A Forbes, Sara E Howden, Kynan Lawlor, Belinda Phipson, Jovana Maksimovic, Lorna Hale, Sean Wilson, Catherine Quinlan, Gladys Ho, Katherine Holman, Bruce Bennetts, Joanna Crawford, Peter Trnka, Alicia Oshlack, Chirag Patel, Andrew Mallett, Cas Simons, Melissa H Little
Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies...
April 21, 2018: American Journal of Human Genetics
https://www.readbyqxmd.com/read/29704304/loss-of-function-ift27-variants-associated-with-an-unclassified-lethal-fetal-ciliopathy-with-renal-agenesis
#14
Chloé Quélin, Philippe Loget, Lucile Boutaud, Nadia Elkhartoufi, Joelle Milon, Sylvie Odent, Mélanie Fradin, Florence Demurger, Laurent Pasquier, Sophie Thomas, Tania Attié-Bitach
Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein-encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c...
April 27, 2018: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/29689222/snare-complex-assembly-and-disassembly
#15
Tae-Young Yoon, Mary Munson
A fundamental hallmark of eukaryotic cells is their compartmentalization into functionally distinct organelles, including those of the secretory and endocytic pathways. Transport of cargo between these compartments and to/from the cell surface is mediated by membrane-bound vesicles and tubules. Delivery of cargo is facilitated by SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor)-mediated membrane fusion of vesicles with their target compartments. Vesicles contain a variety of cargos, including lipids, membrane proteins, signaling molecules, biosynthetic and hydrolytic enzymes, and the trafficking machinery itself...
April 23, 2018: Current Biology: CB
https://www.readbyqxmd.com/read/29688594/whole-genome-sequencing-in-patients-with-ciliopathies-uncovers-a-novel-recurrent-tandem-duplication-in-ift140
#16
Véronique Geoffroy, Corinne Stoetzel, Sophie Scheidecker, Elise Schaefer, Isabelle Perrault, Séverine Bär, Ariane Kröll, Marion Delbarre, Manuela Antin, Anne-Sophie Leuvrey, Charline Henry, Hélène Blanché, Eva Decker, Katja Kloth, Günter Klaus, Christoph Mache, Dominique Martin-Coignard, Steven McGinn, Anne Boland, Jean-François Deleuze, Sylvie Friant, Sophie Saunier, Jean-Michel Rozet, Carsten Bergmann, Hélène Dollfus, Jean Muller
Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases such as the Bardet-Biedl syndrome. Using whole genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27 to 30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole exome sequencing...
April 24, 2018: Human Mutation
https://www.readbyqxmd.com/read/29676541/primary-cilia-as-a-signaling-platform-for-control-of-energy-metabolism
#17
REVIEW
Do Kyeong Song, Jong Han Choi, Min Seon Kim
Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity...
April 2018: Diabetes & Metabolism Journal
https://www.readbyqxmd.com/read/29673930/amelioration-of-neurosensory-structure-and-function-in-animal-and-cellular-models-of-a-congenital-blindness
#18
Ji Yun Song, Puya Aravand, Sergei Nikonov, Lanfranco Leo, Arkady Lyubarsky, Jeannette L Bennicelli, Jieyan Pan, Zhangyong Wei, Ivan Shpylchak, Pamela Herrera, Daniel J Bennett, Nicoletta Commins, Albert M Maguire, Jennifer Pham, Anneke I den Hollander, Frans P M Cremers, Robert K Koenekoop, Ronald Roepman, Patsy Nishina, Shangzhen Zhou, Wei Pan, Gui-Shuang Ying, Tomas S Aleman, Jimmy de Melo, Ilan McNamara, Junwei Sun, Jason Mills, Jean Bennett
Most genetically distinct inherited retinal degenerations are primary photoreceptor degenerations. We selected a severe early onset form of Leber congenital amaurosis (LCA), caused by mutations in the gene LCA5, in order to test the efficacy of gene augmentation therapy for a ciliopathy. The LCA5-encoded protein, Lebercilin, is essential for the trafficking of proteins and vesicles to the photoreceptor outer segment. Using the AAV serotype AAV7m8 to deliver a human LCA5 cDNA into an Lca5 null mouse model of LCA5, we show partial rescue of retinal structure and visual function...
March 21, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29659833/ift172-conditional-knockout-mice-exhibit-rapid-retinal-degeneration-and-protein-trafficking-defects
#19
Priya R Gupta, Nachiket Pendse, Scott H Greenwald, Mihoko Leon, Qin Liu, Eric A Pierce, Kinga M Bujakowska
Intraflagellar transport (IFT) is a bidirectional transport process that occurs along primary cilia and specialized sensory cilia, such as photoreceptor outer-segments. Genes coding for various IFT components are associated with ciliopathies. Mutations in IFT172 lead to diseases ranging from isolated retinal degeneration to severe syndromic ciliopathies. In this study, we created a mouse model of IFT172-associated retinal degeneration to investigate the ocular disease mechanism. We found that depletion of IFT172 in rod photoreceptors leads to a rapid degeneration of the retina, with severely reduced electroretinography responses by one month and complete outer-nuclear layer degeneration by two months...
April 5, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29650680/cell-type-specific-regulation-of-ciliary-transition-zone-assembly-in-vertebrates
#20
Antonia Wiegering, Renate Dildrop, Lisa Kalfhues, André Spychala, Stefanie Kuschel, Johanna Maria Lier, Thomas Zobel, Stefanie Dahmen, Tristan Leu, Andreas Struchtrup, Flora Legendre, Christine Vesque, Sylvie Schneider-Maunoury, Sophie Saunier, Ulrich Rüther, Christoph Gerhardt
Ciliopathies are life-threatening human diseases caused by defective cilia. They can often be traced back to mutations of genes encoding transition zone (TZ) proteins demonstrating that the understanding of TZ organisation is of paramount importance. The TZ consists of multimeric protein modules that are subject to a stringent assembly hierarchy. Previous reports place Rpgrip1l at the top of the TZ assembly hierarchy in Caenorhabditis elegans By performing quantitative immunofluorescence studies in RPGRIP1L-/- mouse embryos and human embryonic cells, we recognise a different situation in vertebrates in which Rpgrip1l deficiency affects TZ assembly in a cell type-specific manner...
April 12, 2018: EMBO Journal
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